Triglyceride-lowering agent and hyperinsulinism-ameliorating agent

ABSTRACT

The present invention is directed to a triglyceride-lowering agent, exhibiting excellent triglyceride-lowering effect and a hyperinsulinemia-ameliorating agent. 
     The triglyceride-lowering agent and hyperinsulinemia-ameliorating agent are characterized by containing a pitavastatin compound, and amlodipine or a salt thereof.

TECHNICAL FIELD

The present invention relates to a triglyceride-lowering agent,exhibiting excellent triglyceride-lowering effect and ahyperinsulinemia-ameliorating agent.

BACKGROUND ART

Triglyceride is the predominant component of blood neutral lipid and,physiologically, is utilized as an energy source in the peripheraltissue. Hypertriglyceridemia, involving an increased blood triglyceridelevel, is thought to be a risk factor of arteriosclerosis, and actuallyis employed as a diagnostic standard for metabolic syndrome. Therefore,for patients suffering or suspected of suffering hypertriglyceridemia,blood triglyceride is desirably lowered to an appropriate level by useof a drug or through other methods.

Hyperinsulinemia is a disease caused by over-secretion of insulin fromthe islets of Langerhans of the pancreas, which over-secretioncompensates hyperglycemia occurring in diabetes or a pre-diabetes stage.When insulin has been over-secreted, pancreatic hormone secretionability and sugar-utilization in the peripheral tissue are impaired, andblood insulin is maintained at high level, thereby causing a variety ofcomplications. For example, retinopathy, aggravation of nephropathy, andinduction of differentiation of fat cells and other cells occur.Therefore, amelioration of hyperinsulinemia is effective for theprevention of such complications and obesity, particularly prevention ofaccumulation of visceral fat. Thus, there is the demand for ahigh-efficacy hyperinsulinemia-ameliorating agent.

The aforementioned pathological conditions and diseases are closelyrelated to metabolic syndrome, whose diagnosis standards have recentlybeen published, and are classified as life-style-related diseasesincluding hyperlipidemia. According to the diagnosis standard, metabolicsyndrome is defined as a condition in which visceral-fat-increasedobesity is complicated with two or more of hyperglycemia, hypertension,and hyperlipidemia.

Statins (HMG-CoA reductase inhibitors) are administered tohyperlipidemia patients, since intense cholesterol-lowering actionthereof is expected.

Statins are known to have an action on neutral lipid; specifically, aslight triglyceride-lowering action concomitant with acholesterol-lowering action (see, for example, Non-Patent Document 1).However, when statin is used singly, triglyceride-lowering actionthereof is insufficient. Thus, there has been proposed use of statin incombination with a triglyceride-lowering agent; for example, afibrate-type drug. However, rhabdomyolysis has been reported to occur asan adverse side effect mainly in kidney disorder patients, when such afibrate-type drug having strong triglyceride-lowering action and statinare used in combination. Thus, this combined administration must becarried out very carefully.

Statins are also known to have an action on insulin; specifically, aslight insulin-resistance-ameliorating action concomitant with acholesterol-lowering action (see, for example, Non-Patent Document 2).However, no effect of statins has been known to amelioratehyperinsulinemia. When statin is used singly, the insulin-resistanceameliorating action thereof is insufficient. Thus, there have beenproposed the use of statin in combination with otherinsulin-resistance-ameliorating agents such as metformin or glitazonesand use thereof in combination with a hypoglycemic agent such as asulfonylurea agent. However, when statin is used with another agent suchas an insulin-resistance-ameliorating agent or a hypoglycemic agent,control of blood sugar level is difficult, possibly causing a fatalhypoglycemia condition. Thus, this combined administration must also becarried out very carefully.

Generally, in many patients suffering hyperlipidemia, diabetes,metabolic syndrome, etc., hypertriglyceridemia occurs due to obesity orimpairment in a metabolic function.

Also, hyperinsulinemia occurs in many cases due to insulin secretionhyperfunction of the pancreas, which hyperfunction compensates forhyperglycemia. Therefore, there has been the demand for a drug whichreduces adverse side effects and which promotes effectivetriglyceride-lowering action, as well as the demand for a drug whichpromotes hyperinsulinemia-ameliorating action, which drugs are used incombination with stain serving as a hyperlipidemia-treating agent.

Meanwhile, calcium antagonist is employed as a therapeutic agent forhypertension and angina pectoris, but neither triglyceride-loweringaction nor hyperinsulinemia-ameliorating action is envisaged in usethereof, in view of the action mechanism of the antagonist. Furthermore,amlodipine besylate—a type of calcium antagonist—has been reported toincrease the triglyceride level of hypertension patients (see Non-PatentDocument 3). Also, amlodipine has been reported to give no significanteffect on the plasma triglyceride level of hypertension patients (seeNon-Patent Document 4). In animal models, when administered tofructose-loaded hypertriglyceridemia rats, amlodipine besylate has nosignificant triglyceride-lowering action orhyperinsulinemia-ameliorating action (see Non-Patent Document 5).

Notably, the main action of calcium antagonist is a hypotensive activityon the basis of selectively binding to cell membrane potential-dependentcalcium channel, reducing flow of calcium ions into cells, and relaxingsmooth muscle of coronary and peripheral vessels. Hitherto, directlipid-decomposing action has not been reported, nor has insulinbiosynthesis, secretion, and decomposing action.

Statin has a cholesterol-lowering action, whereas a calcium antagonisthas a hypotensive action. Therefore, in the clinical field, the twoagents are administered in combination to patients suffering from bothhyperlipidemia and hypertension. Some scientific documents reportadministration of atorvastatin and amlodipine in combination to patientssuffering from a coronary arterial disease. In the studies, there hasbeen found no difference between a plasma triglyceride level of thecombined administration group and that of an atorvastatin singleadministration group (see Non-Patent Documents 6 and 7). In addition,these documents do not disclose plasma insulin level. Similarly, inanimal models (genetically modified mice), no difference has been foundbetween the plasma triglyceride level of an atorvastatin singleadministration group and that of an atorvastatin-amlodipine combinedadministration group (see Non-Patent Document 8). The document does notdescribe that the combined administration gives an effect on the plasmainsulin level. Some patent publications (Laid-Open) disclose combinedadministration of statin and amlodipine (see Patent Documents 1 to 3).However, these patent documents are silent regarding the effects ofcombined administration of statin and a calcium antagonist on thetriglyceride-lowering action and on hyperinsulinemia.

Patent Document 1:

International Publication WO99/11259, pamphlet

Patent Document 2:

International Publication WO99/11260, pamphlet

Patent Document 3:

International Publication WO99/11263, pamphlet

Non-Patent Document 1:

Clin. Cardiol., 19(9): 683-9, 1996

Non-Patent Document 2: Therapeutic Research, 24: 1383-1389, 2003Non-Patent Document 3:

Curr. Med. Res. Opin., 21(6): 951-8, 2005

Non-Patent Document 4:

Br. J. Clin. Pharmacol., 39(5): 471-6, 1995

Non-Patent Document 5: Hypertension, 45: 1012-18, 2005 Non-PatentDocument 6:

Am. J. Hypertension, 17: 823-827, 2004

Non-Patent Document 7:

Am. J. Cardiol., 95: 249-253, 2005

Non-Patent Document 8:

J. Mol. Cell. Cardiol., 35: 109-118, 2003

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a drug having excellenttriglyceride-lowering action and hyperinsulinemia-ameliorating actionand providing reduced adverse side effects.

Means for Solving the Problems

In view of the foregoing, the present inventors have conducted extensivestudies and, surprisingly, have found that remarkabletriglyceride-lowering action and hyperinsulinemia-ameliorating actioncan be obtained through employment in combination of a pitavastatincompound such as pitavastatin calcium and amlodipine—known as a calciumantagonist—or a salt thereof. The present invention has beenaccomplished on the basis of this finding.

Accordingly, the present invention provides a triglyceride-loweringagent, characterized by containing a pitavastatin compound, andamlodipine or a salt thereof.

The present invention also provides a preventive and/or therapeuticagent for hypertriglyceridemia, characterized by containing apitavastatin compound, and amlodipine or a salt thereof.

The present invention also provides a hyperinsulinemia-amelioratingagent, characterized by containing a pitavastatin compound, andamlodipine or a salt thereof.

The present invention also provides a preventive and/or therapeuticagent for hyperinsulinemia, characterized by containing a pitavastatincompound, and amlodipine or a salt thereof.

The present invention also provides a metabolic-syndrome-amelioratingagent, characterized by containing a pitavastatin compound, andamlodipine or a salt thereof.

The present invention also provides a preventive and/or therapeuticagent for metabolic syndrome, characterized by containing a pitavastatincompound, and amlodipine or a salt thereof.

The present invention also provides a method for lowering triglyceride,characterized by comprising administering a pitavastatin compound, andamlodipine or a salt thereof to a subject in need thereof.

The present invention also provides a method for prevention and/ortreatment of hypertriglyceridemia, characterized by comprisingadministering a pitavastatin compound, and amlodipine or a salt thereofto a subject in need thereof.

The present invention also provides a method for amelioratinghyperinsulinemia, characterized by comprising administering apitavastatin compound, and amlodipine or a salt thereof to a subject inneed thereof.

The present invention also provides a method for prevention and/ortreatment of hyperinsulinemia, characterized by comprising administeringa pitavastatin compound, and amlodipine or a salt thereof to a subjectin need thereof.

The present invention also provides a method for ameliorating metabolicsyndrome, characterized by comprising administering a pitavastatincompound, and amlodipine or a salt thereof to a subject in need thereof.

The present invention also provides a method for prevention and/ortreatment of metabolic syndrome, characterized by comprisingadministering a pitavastatin compound, and amlodipine or a salt thereofto a subject in need thereof.

The present invention also provides use of a pitavastatin compound, andamlodipine or a salt thereof for producing a triglyceride-loweringagent.

The present invention also provides use of a pitavastatin compound, andamlodipine or a salt thereof for producing a preventive and/ortherapeutic agent for hypertriglyceridemia.

The present invention also provides use of a pitavastatin compound, andamlodipine or a salt thereof for producing ahyperinsulinemia-ameliorating agent.

The present invention also provides use of a pitavastatin compound, andamlodipine or a salt thereof for producing a preventive and/ortherapeutic agent for hyperinsulinemia.

The present invention also provides use of a pitavastatin compound, andamlodipine or a salt thereof for producing ametabolic-syndrome-ameliorating agent.

The present invention also provides use of a pitavastatin compound, andamlodipine or a salt thereof for producing a preventive and/ortherapeutic agent for metabolic syndrome.

EFFECTS OF THE INVENTION

According to the present invention, there can be provided atriglyceride-lowering agent and a preventive and/or therapeutic agentfor hypertriglyceridemia, exhibiting excellent triglyceride-loweringeffect and less adverse side effects. According to the presentinvention, there can be provided a hyperinsulinemia-ameliorating agentand a preventive and/or therapeutic agent for hyperinsulinemia,exhibiting excellent hyperinsulinemia-ameliorating effect and lessadverse side effects. According to the present invention,hypertriglyceridemia and hyperinsulinemia of a hyperlipidemia patientcan be effectively prevented and/or treated through administration of apitavastatin compound, and amlodipine or a salt thereof in combination.According to the present invention, prevention and treatment ofmetabolic syndrome and ameliorating the condition of metabolic syndromecan be realized.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: A graph showing an effect of single or combined administrationof pitavastatin calcium (described simply as pitavastatin) andamlodipine besylate (described simply as amlodipine) on plasmatriglyceride level.

FIG. 2: A graph showing an effect of single or combined administrationof pitavastatin calcium (described simply as pitavastatin) andamlodipine besylate (described simply as amlodipine) on plasma insulinlevel.

BEST MODES FOR CARRYING OUT THE INVENTION

The pitavastatin compound employed in the present invention encompassespitavastatin, a salt thereof, a lactone form thereof, a hydrate of anyof these, and a solvate of any of these with the solvent which ispharmaceutically acceptable. The pitavastatin compound has a cholesterolsynthesis inhibitory activity based on inhibition of HMG-CoA reductaseand is known to serve as a hyperlipidemia therapeutic agent. Examples ofthe salt of pitavastatin include alkali metal salts such as a sodiumsalt and a potassium salt; alkaline earth metal salts such as a calciumsalt and a magnesium salt; organic amine salts such as a phenethylaminesalt; and an ammonium salt. Of these, salts of pitavastatin ispreferred, with the calcium salt and the sodium salt being particularlypreferred.

The pitavastatin compound may be produced through a method disclosed inU.S. Pat. No. 5,856,336 or in Japanese patent Application Laid-Open(kokai) No. 1-279866.

As mentioned above, the amlodipine or a salt thereof employed in thepresent invention is a calcium antagonist.

Among these species, amlodipine besylate is readily available as acommercial product. No particular limitation is imposed on the salt ofamlodipine, so long as the salt is pharmaceutically acceptable. Examplesof the salt include inorganic acid salts such as hydrochloride, sulfate,nitrate, hydrobromide, and phosphate; and organic acid salts such asacetate, trifluoroacetate, fumarate, maleate, lactate, tartrate,citrate, succinate, malonate, methanesulfonate, p-toluenesulfonate,besylate (benzenesulfonate), camsylate (camphorsulfonate),ethanesulfonate, and nicotinate. Of these, besylate and camsylate arepreferred, with besylate being particularly preferred.

According to the present invention, a pitavastatin compound, andamlodipine or a salt thereof are administered in combination. As shownin the Example hereinbelow, when a pitavastatin compound, and amlodipineor a salt thereof are administered in combination to fructose-loadedhypertriglyceridemia rats (evaluation group), the plasma triglyceridelevel and the plasma insulin level are considerably lowered, andhypertriglyceridemia and hyperinsulinemia are ameliorated, as comparedwith the case where each of the two agent is singly administered.Therefore, the drug of the present invention is useful for theprevention and/or treatment of hypertriglyceridemia andhyperinsulinemia.

The pitavastatin compound and amlodipine or a salt thereof contained inthe drug of the present invention may be administered through a routeappropriately selected in accordance with conditions of a patient inneed thereof. Any of the dosage forms including powder, granules, drysyrup, tablets, capsules, and injections may be employed. The dosageforms may be produced by blending a pitavastatin compound, andamlodipine or a salt thereof with a pharmaceutically acceptable carrier,and processing through a routine method known to people in the art.

In one preparation procedure of an oral solid formulation, a vehicle andan optional additive such as a binder, a disintegrant, a lubricant, acolorant, a sweetening agent, or a flavoring agent, are added to theagents, and the mixture is processed, through a routine method, intotables, granules, powder, capsules, etc. Such additives may be thosegenerally employed in the art. Examples of the vehicle include lactose,sodium chloride, glucose, starch, microcrystalline cellulose, andsilicic acid. Examples of the binder include water, ethanol, propanol,simple syrup, gelatin liquid, hydroxypropyl cellulose, methyl cellulose,ethyl cellulose, shellac, calcium phosphate, and poly(vinylpyrrolidone).Examples of the disintegrant include agar powder, sodiumhydrogencarbonate, sodium lauryl sulfate, and stearyl monoglyceride.Examples of the lubricant include purified talc, a stearic acid salt,borax, and polyethylene glycol. Examples of the colorant includeβ-carotene, yellow iron sesquioxide, and caramel. Examples of thesweetening agent include sucrose and bitter orange peel.

In one preparation procedure of an oral liquid formulation, an additivesuch as a sweetening agent, a buffer, a stabilizer, or a preservative isadded to the agents, and the mixture is processed, through a routinemethod, into oral liquid, syrup, elixir, etc. Such additives may bethose generally employed in the art. Examples of sweetening agentsinclude sucrose. Examples of the buffer include sodium citrate. Examplesof the stabilizer include traganth. Examples of the preservative includep-oxybenzoic acid ester.

In one preparation procedure of an injection, a pH-regulator, astabilizer, a tonicity agent, etc. are added to the agents, and themixture is processed, through a routine method, into subcutaneous,intramuscular, and intravenous injections. Such additives may be thosegenerally employed in the art. Examples of the pH-regulator includesodium phosphate. Examples of the stabilizer include sodium pyrosulfite.Examples of the tonicity agent include sodium chloride.

No particular limitation is imposed on the mode of administration of thedrug of the present invention. The two agents may be administeredsimultaneously, or separately with an interval. In other words, apitavastatin compound, and amlodipine or a salt thereof may beformulated into a single drug, or may be separately formed into drugproducts, which may be incorporated in combination into a kit. When thetwo agents are formed into separate drug products, these drug productsdo not necessarily have the same drug form. These agents may beadministered at different frequencies.

In the present invention, when a single drug containing the two agentsis administered, the ratio by mass of the pitavastatin compound toamlodipine or a salt thereof is preferably 1:0.05 to 1:50, morepreferably 1:0.1 to 1:10.

In the present invention, the dose of each agent is appropriatelyselected in accordance with the condition of the patient to which theagent is administered, so long as the dose is an effective amount.Preferably, the daily dose of a pitavastatin compound is 0.01 to 50 mg,more preferably 0.1 to 10 mg, while the daily dose of amlodipine or asalt thereof is preferably 1 to 50 mg, more preferably 2.5 mg to 20 mg.The administration may be once a day or may be divided into twice ormore.

EXAMPLES

The present invention will next be described in more detail by way ofexample, which should not be construed as limiting the inventionthereto.

Example 1

Pitavastatin calcium (hereinafter referred to simply as pitavastatin)and amlodipine besylate (hereinafter referred to simply as amlodipine)were administered in combination to a subject, and plasmatriglyceride-lowering action and hyperinsulinemia-ameliorating actionwere evaluated through the following test procedure.

1. Tested Animal and Breeding Conditions

Male Sprague Dawley rats aged 7 weeks (Clea Japan, Inc.) were fed in abreeding room in which a bright dark cycle was maintained (brightduration by a room light: 7 a.m. to 7 p.m.) at a temperature and ahumidity of 23±3° C. and 55±15% throughout the test period. The ratswere allowed to take a solid chow (CE2; product of Oriental Yeast Co.,Ltd.) and 25% aqueous fructose, ad libitum.

2. Drug Preparation

Each of pitavastatin and amlodipine was suspended in 1.0-mass % aqueoussolution of hydroxypropylmethyl cellulose (product of Shin-Etsu ChemicalCo., Ltd.) in such an amount that the dose thereof was adjusted to 1mL/kg. The suspension was refrigerated at 4° C. in a shaded bottle. Eachdrug was prepared every 7 days.

3. Test Method

After the rats had been fed ad libitum with 25% aqueous fructose for twoweeks, plasma triglyceride level was measured by means of a TriglycerideE Test Wako (product of Wako Pure Chemical Industries, Ltd.). Among therats, those having undesirably low plasma triglyceride levels wereremoved, and the following groups were provided. Specifically, 48 ratswere divided into four groups (each including 12 rats) such that theaverage plasma triglyceride levels were equalized. The four groups were(1) a control group, (2) a pitavastatin alone (10 mg/kg)-administrationgroup, (3) an amlodipine alone (15 mg/kg)-administration group, and (4)a pitavastatin (10 mg/kg) and amlodipine (15 mg/kg)-combinedadministration group.

Pitavastatin and amlodipine were orally administered once a day (4 p.m.)repeatedly for 21 days. To the control group, a 1.0-mass % aqueoussolution of hydroxypropylmethyl cellulose sodium was orally administeredat 1 mL/kg once a day (4 p.m.). For each group, blood was collected fromeach rat 22 hours after final administration, and the plasmatriglyceride level was measured by means of a Triglyceride E Test Wako(product of Wako Pure Chemical Industries, Ltd.), and the plasma insulinlevel was measured by means of a Levis insulin kit (product of ShibayagiCo., Ltd.).

4. Statistical Analysis and Data Processing Method

The determined average levels of each group are represented by averagevalue±standard deviation. The difference between each administrationgroup and the control group was analyzed through Dunnett's parametrictest, and P values of 5% or less (p<0.05) were considered statisticallysignificant. The synergistic effect was evaluated in accordance with theBurgi formula.

FIGS. 1 and 2 show the results. As shown in FIG. 1, plasma triglyceridelevels of the pitavastatin alone group and the amlodipine alone groupwere almost equivalent to those of the control group. In contrast,through administration of the two agents in combination, the plasmatriglyceride level was significantly lowered (p<0.01). Throughcalculation with the Burgi formula, the relative plasma triglyceridelevel of the pitavastatin-amlodipine combination group (0.554, based onthe control group) was lower than the product of the relative levels ofthe agent alone groups (0.966×0.831=0.803), thereby confirming asynergistic lowering effect.

As shown in FIG. 2, plasma insulin levels of the pitavastatin alonegroup and the amlodipine alone group were not significantly changed ascompared with the control group. In contrast, the plasma insulin levelwas significantly lowered (p<0.05) through the combined administration.Through calculation with the Burgi formula, the relative plasma insulinlevel of the pitavastatin-amlodipine combination group (0.657, based onthe control group) was lower than the product of the relative levels ofthe agent alone groups (0.971×0.771=0.749), confirming a synergisticlowering effect.

Therefore, combined administration of pitavastatin and amlodipine wasfound to exhibit a remarkably excellent effect of lowering plasmatriglyceride level and plasma insulin level, as compared with the caseswhere the respective agents were administered alone.

1-18. (canceled) 19: A method for lowering triglyceride, comprisingadministering a therapeutically effective amount of a pitavastatincompound, and amlodipine or a salt thereof to a subject in need thereof.20: The method for lowering triglyceride as described in claim 19,wherein the pitavastatin compound is pitavastatin calcium. 21: Themethod for lowering triglyceride as described in claim 19, wherein thesalt of amlodipine is amlodipine besylate. 22: A method for treatment ofhypertriglyceridemia, comprising administering a therapeuticallyeffective amount of a pitavastatin compound, and amlodipine or a saltthereof to a subject in need thereof. 23: The therapeutic method asdescribed in claim 22, wherein the pitavastatin compound is pitavastatincalcium. 24: The therapeutic method as described in claim 22, whereinthe salt of amlodipine is amlodipine besylate. 25: A method forameliorating hyperinsulinemia, comprising administering atherapeutically effective amount of a pitavastatin compound, andamlodipine or a salt thereof to a subject in need thereof. 26: Themethod for ameliorating hyperinsulinemia as described in claim 25,wherein the pitavastatin compound is pitavastatin calcium. 27: Themethod for ameliorating hyperinsulinemia as described in claim 25,wherein the salt of amlodipine is amlodipine besylate. 28: A method fortreatment of hyperinsulinemia, comprising administering a pitavastatincompound, and amlodipine or a salt thereof to a subject in need thereof.29: The therapeutic method as described in claim 28, wherein thepitavastatin compound is pitavastatin calcium. 30: The therapeuticmethod as described in claim 28, wherein the salt of amlodipine isamlodipine besylate. 31: A method for ameliorating metabolic syndrome,comprising administering a therapeutically effective amount of apitavastatin compound, and amlodipine or a salt thereof to a subject inneed thereof. 32: The method for ameliorating metabolic syndrome asdescribed in claim 31, wherein the pitavastatin compound is pitavastatincalcium. 33: The method for ameliorating metabolic syndrome as describedin claim 31, wherein the salt of amlodipine is amlodipine besylate. 34:A method for treatment of metabolic syndrome, comprising administering atherapeutically effective amount of a pitavastatin compound, andamlodipine or a salt thereof to a subject in need thereof. 35: Thetherapeutic method as described in claim 34, wherein the pitavastatincompound is pitavastatin calcium. 36: The therapeutic method asdescribed in claim 34, wherein the salt of amlodipine is amlodipinebesylate. 37-54. (canceled)